rFVII for pediatric acute intracranial hemorrha

rFVII for Pediatric Acute Intracranial Hemorrhage To the Editor: A recent interesting phase IIB randomized, double-blind, placebo-controlled, dose-ranging “proof-of-concept” trial on rec

Frederic Perez-Alvarez, Cristina Serra, Jaume Macia and Lluis Mayol

rFVII for Pediatric Acute Intracranial Hemorrhage

Print ISSN: 0039-2499 Online ISSN: 1524-4628 Copyright © 2007 American Heart Association, Inc All rights reserved.

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rFVII for Pediatric Acute

Intracranial Hemorrhage

To the Editor:

A recent interesting phase IIB randomized, double-blind,

placebo-controlled, dose-ranging “proof-of-concept” trial on

recom-binant activated factor VII (rFVIIa) for acute intracranial

hemor-rhage in adult patients has been reported.1 A lacking of similar

experience in the pediatric population is noted rFVIIa has been

anecdotally reported as effective for profound bleeding episodes in

children In the pediatric literature, case reports have been made

with apparent clinical improvement seen after the use of rFVIIa for

acute life-threatening bleeding; however, there are limited data

regarding its use in infants younger than 4 months of age, regardless

of whether it is a congenital or acquired condition.2–3

We report on a case of acute intracranial hemorrhage in a

newborn with congenital factor VII deficiency treated with

rFVIIa and given a prophylactic program during a follow-up of

36 months A full-term newborn boy, the first child of nonrelated

black parents, was born to his mother aged 29, and the father was

28 years old The family history was unremarkable The

preg-nancy was uneventful Her birth weight was 2800 g, height was

47.0 cm, and cranial perimeter was 33 cm Apgar scores were

5 and 6 at 1 and 5 minutes, respectively Multifocal seizures

occurred on the second day postpartum The fontanelle was

tense, and the cerebrospinal was bloody Cranial CT did not

show abnormal parenchymal images Subarachnoid hemorrhage

was diagnosed Posthemorrhagic hydrocephalus occurred later,

and she required shunt placement Tests for coagulopathies

reveled factor VII deficiency rFVIIa was given 150␮g/kg The

patient received a prophylactic treatment with an infusion

pro-gram every 3 days in which she received rFVIIa using multiple

doses from a single reconstituted vial over a 72-hour period

Since then, coagulation has been tested every 3 months and 80

␮g/kg intravenous rFVIIa is given if prothrombin time is ⬍30%

At the age of 4 months, he was admitted because of increased

intracranial pressure and a temporoparietal hematoma was

iden-tified on CT of the brain, with the prothrombin time being of

30% After a follow-up of 30 months, rFVIIa was required twice

according to this scheme No further hemorrhagic complications

have occurred, with no change in prophylactic program

Devel-opmental retardation is present At 36 months old, MRI shows

residual parenchymal lesion Family study was uneventful

Factor VII deficiency is the least rare among uncommon

congen-ital coagulation disorders The majority of cases are isolated

defi-ciencies Curiously, we remark that subarachnoid hemorrhage in

adults has been previously reported.4

Some practical questions are raised First, we report on rFVIIa

treatment and prophylaxis of bleeding in congenital deficiency

However, conclusions and hypotheses can be drawn from it

independently of the congenital or acquired bleeding condition

Recombinant FVIIa has been reported to provide effective

hemo-stasis in patients of all ages and in a range of bleeding situations,

including acute central nervous system/life-threatening bleeding

episodes, nonlife-threatening bleeding episodes, surgery, and

childbirth It may also promote hemostasis in patients with

normal coagulation rFVa acts locally at the bleeding site without

activating systemic coagulation Reports suggest that it may also

be effective prophylactically However, the risk of thrombosis in FVII-deficient patients treated with rFVIIa is unknown, as is the occurrence of inhibiting antibodies.5

Second, we do not know exactly the doses for both treatment and prophylaxis Nor do we know if doses for both congenital and acquired condition are the same Effect was reached with all

3 doses that were tested (40, 80, and 160␮g/kg).1A phase III trial comparing 20 and 80␮g/kg rFVIIa with placebo is now in progress However, physiological differences in the hemostatic system between children and adults have been reported6 The most commonly used dose is 90␮g/kg body weight rFVIIa as bolus, and, if necessary, followed by additional injections at intervals of 2 to 3 hours In factor VII deficiency, lower dosages

of 15 to 30␮g/kg body weight of rFVIIa are given every 4 to 6 hours, whereas higher doses of 150 to 200␮g/kg body weight are used in neonates

We do not know the exact level of coagulability to guarantee

a nonhemorrhagic diathesis condition in case of factor VII deficiency In fact, a reported 65-year-old patient with congenital isolated factor VII deficiency and bleeding problems had not shown earlier bleeding problems, presumably because of com-pensation for the factor VII deficiency by enhanced activities of components of the extrinsic coagulation pathway, factors II, VIII,

IX, and X.7

Third, the use of rFVIIa in hemorrhagic shock in neonates and preterm infants are increasing For instance, neonates with massive postsurgical hemorrhage after ileostomy, with severe pulmonary hemorrhage in the course of mechanical ventilation for meconium aspiration syndrome, with congenital heart dis-ease Also, during postoperative resuscitation after cardiac sur-gery for congenital heart disease in which multiple administra-tion of rFVIIa (120␮g/kg per dose) and antifibrinolytic therapy, aminocaproic acid (100 mg/kg per dose), were successfully used.8

Prevention of intraventricular hemorrhage and its potential long-term sequelae remain one of the major challenges in the early management of preterm infants rVIIa, a novel hemostatic agent with an ever-expanding list of potential applications, warrants consideration for use in this setting The hypothesis that early prophylactic administration of rVIIa to extremely preterm infants (⬍28 weeks) would reduce the incidence of severe intraventricular hemorrhage needs to be tested.9

Finally, intracerebral hemorrhage causes severe disability and

a staggering economic burden Because rFVIIa is a very expen-sive therapy, possible strategies for optimizing its use in these settings in the pediatric population are particularly needed.10

Disclosures

None

Frederic Perez-Alvarez, MD

NeuroPediatric Unit Hospital ICS Universitari Dr J Trueta

Girona, Spain

(Stroke 2007;38:e63-e64.)

© 2007 American Heart Association, Inc

Stroke is available at http://www.strokeaha.org DOI: 10.1161/STROKEAHA.107.484493

e63

Letters to the Editor

by guest on February 11, 2014 http://stroke.ahajournals.org/

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Cristina Serra, MB Jaume Macia, MD Lluis Mayol, MD

Pediatric Department Hospital ICS Universitari Dr J Trueta

Girona, Spain

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factor VIIa for treatment of massive liver fracture in a premature infant.

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4 Papa ML, Schisano G, Franco A, Nina P Congenital deficiency of factor

VII in subarachnoid hemorrhage Stroke 1994;25:508 –510.

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Haemophilia 2006;12:19 –27.

6 Sosothikul D, Seksarn P, Lusher JM Pediatric REFERENCE values for

molecular Markers in Hemostasis J Pediatr Hematol Oncol 2007;29:19 –22.

7 Tsuda T, Okamoto Y, Sakaguchi R, Katayama N, Ota K Isolated factor

VII deficiency diagnosed after a life-threatening brain haemorrhage J Int

Med Res 2000;28:318 –323.

8 Grizelj R, Vukovic J, Filipovic-Groic B, Saric D, Luetic T Successful use

of recombinant activated FVII and aminocaproic acid in four neonates

with life-threatening hemorrhage Blood Coagul Fibrinolysis 2006;17:

413– 415.

9 Robertson JD Prevention of intraventricular haemorrhage: a role for

recom-binant activated factor VII J Paediatr Child Health 2006;42:325–331.

10 Earnshaw SR, Joshi AV, Wilson MR, Rosand J Cost-effectiveness of recombinant activated factor VII in the treatment of intracerebral

hem-orrhage Stroke 2006;37:2751–2758.

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